The new era in cancer drug development represents a paradigm shift in how early phase studies are conducted relative to the ?conventional? approach of treating without consideration to underlying tumor genomics, biology and immunology. Translational endpoints, including levels of target expression, engagement, and modulation of downstream effectors are being assessed as early as possible, and increasing emphasis is being placed on early patient selection, utilizing novel biomarker assays and molecular characterization to identify patients most likely to respond. The ultimate purpose of the NCI Experimental Therapeutics-Clinical Trials Network (ETCTN) is to develop new therapeutic options while also defining better approaches for the development of novel anticancer agents that capitalize on the ability to characterize tumors molecularly and by also finding appropriate biomarkers to select patients most likely to respond. As biomarker-driven trials become the cornerstone of early phase investigation, allowing for the study of potential mechanisms of response and resistance, incorporation of these biomarkers is lending itself to novel trial designs which incorporate fewer, and often rarer patient subsets, defining greater patient outcomes with smaller recruited populations. As a result, a unique network such as the ETCTN, consisting of multiple scientifically-driven sites and investigators with a vast array of expertise, is needed. The ETCTN allows investigators to test relevant bench-to-bedside findings, and through integrated analysis and the development of interdisciplinary teams, incorporates reverse translation to bring the bedside back to the bench. This application is a re-competition of our previous ETCTN UM1 award (1UM1CA186689), demonstrating both our progress over the past funding period as well as our capabilities to conduct early phase clinical trials. We have slightly amended our original partnerships which now include Vanderbilt-Ingram, University of California San Diego, Karmanos Cancer Institute, University of Oklahoma Stephenson Cancer Center (new) and the Yale Cancer Center (VICKtOrY). Our team aims to 1) leverage novel scientific discoveries for translation into early phase trials, using the CTEP pharmacopeia, in rare cancers, common cancers, and uncommon variants of common cancers; 2) incorporate serum, tissue and imaging biomarkers to better understand the effects of novel agents either alone or in combination; 3) train early career investigators to be knowledgeable and proficient in conducting early phase clinical trials by providing clinical research leadership opportunities and mentoring; and 4) include as a component of our early phase clinical trial recruitment, no less than 10% underserved/special populations. The members of our team have a unique set of complementary expertise and a similar philosophy regarding collaborative research and mentorship of the next generation of cancer investigators. VICKtOrY is committed to utilizing our areas of expertise, integrating the science at our institutions, and maximizing our collaborative relationships to conduct cutting-edge early phase trials within the ETCTN with the ultimate mission of improving outcomes for cancer patients.